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D designed the experiments: AN YO KI MY. Performed the experiments

D designed the experiments: AN YO KI MY. Performed the experiments: YO KI. Analyzed the data: YO KI TK WT YS SK HM SM YN KF HK. Contributed reagents/materials/analysis tools: KW SS. Wrote the paper: AN YO KI MY.needed to fully investigate the diagnostic and therapeutic implications of our findings.AcknowledgmentsThe skillful technical assistance of Machiko Hiraga and Tamiyo Taniguchi is gratefully acknowledged. All authors read and approved the final manuscript.Gastric cancer remains one of the leading causes of cancer death worldwide [1,2]. The standard first-line chemotherapy regimen for locally advanced or metastatic gastric cancer is platinum (cisplatin or oxaliplatin, Pt) and 5-FU combined with other drugs, including docetaxel and irinotecan (CPT-11) [3]; however, median survival remains meager ?around one year. Personalized chemotherapy based on the mRNA expression of predictive biomarkers can maximize efficacy. Meanwhile, development of novel methods and potential anticancer drugs may improve the response rate and efficiency. Title Loaded From File polyphyllin I (PPI), a small molecular monomer extracted from Rhizoma of Paris polyphyllin, is a steroidal saponin (Figure 1) [4]. In China, the rhizome of P. polyphylla, known as Chong-Lou, isreported to have effects on many tumor cells and xenografts, including the pancreas, urinary bladder, 16985061 breast cancer, liver tumor and lung cancer, showing strong anticancer effects in previous studies[4?]. Evodiamine (EVO) [8], a kind of alkaloid from Evodia rutaecarpa (Figure 1), has been reported to inhibit the invasion and metastasis of tumors and induces cell death in several types of cancer cell lines including human acute leukemia CCRF-CEM cells [9], human androgen independent prostate cancer PC-3 cells [10], human breast cancer MCF-7 cells [11], human melanoma A375-S2 cells [12], and murine fibrosarcoma L929 cells [13]. In addition, it has also been reported that EVO caused the mitotic arrest and a consequent apoptosis in CCRF-CEM cells through the enhancement of polymerised tubulin levels [14].Synergistic Anticancer Effects of PPI and EVOFigure 1. The chemical structure of PPI and EVO. PPI molecular weight: 855.02; molecular structure: C44H70O16. EVO molecular weight: 303.36; molecular structure: C19H17N3O. doi:10.1371/journal.pone.0065164.gTo date, studies demonstrating the anticancer activity of PPI and EVO have mainly been done with established cell lines. In the current study, we reported the cytotoxicity effect of PPI and EVO on freshly-removed gastric tumor tissues. To elucidate the mechanisms possibly involved, the expression levels of some associated genes were also determined.Materials and MethodsAll research involving human participants have been approved by the Human Research Protective Committee of Drum Tower Hospital Affiliated to Medical School of Nanjing University and written informed consent was obtained from all patients.specimens included 60 freshly-removed gastric tumors. The study design is shown in Figure 2. Generally speaking, each tumor tissue was divided into two parts once it removed in the surgery: (1) one part was kept in 4uC Hanks’ balanced salt solution with 1 penicillin/streptomycin and detected chemosensitivity in vitro by histoculture drug response assay (HDRA); (2) the rest part was left in formalin and made into Mental Domain (DD). In this study we characterise an interaction between formalin-fixed paraffin-embedded (FFPE) tumor blocks for pathological observation and gene detection. Diagnosis of patients with gastric tumor was confirmed by histopa.D designed the experiments: AN YO KI MY. Performed the experiments: YO KI. Analyzed the data: YO KI TK WT YS SK HM SM YN KF HK. Contributed reagents/materials/analysis tools: KW SS. Wrote the paper: AN YO KI MY.needed to fully investigate the diagnostic and therapeutic implications of our findings.AcknowledgmentsThe skillful technical assistance of Machiko Hiraga and Tamiyo Taniguchi is gratefully acknowledged. All authors read and approved the final manuscript.Gastric cancer remains one of the leading causes of cancer death worldwide [1,2]. The standard first-line chemotherapy regimen for locally advanced or metastatic gastric cancer is platinum (cisplatin or oxaliplatin, Pt) and 5-FU combined with other drugs, including docetaxel and irinotecan (CPT-11) [3]; however, median survival remains meager ?around one year. Personalized chemotherapy based on the mRNA expression of predictive biomarkers can maximize efficacy. Meanwhile, development of novel methods and potential anticancer drugs may improve the response rate and efficiency. Polyphyllin I (PPI), a small molecular monomer extracted from Rhizoma of Paris polyphyllin, is a steroidal saponin (Figure 1) [4]. In China, the rhizome of P. polyphylla, known as Chong-Lou, isreported to have effects on many tumor cells and xenografts, including the pancreas, urinary bladder, 16985061 breast cancer, liver tumor and lung cancer, showing strong anticancer effects in previous studies[4?]. Evodiamine (EVO) [8], a kind of alkaloid from Evodia rutaecarpa (Figure 1), has been reported to inhibit the invasion and metastasis of tumors and induces cell death in several types of cancer cell lines including human acute leukemia CCRF-CEM cells [9], human androgen independent prostate cancer PC-3 cells [10], human breast cancer MCF-7 cells [11], human melanoma A375-S2 cells [12], and murine fibrosarcoma L929 cells [13]. In addition, it has also been reported that EVO caused the mitotic arrest and a consequent apoptosis in CCRF-CEM cells through the enhancement of polymerised tubulin levels [14].Synergistic Anticancer Effects of PPI and EVOFigure 1. The chemical structure of PPI and EVO. PPI molecular weight: 855.02; molecular structure: C44H70O16. EVO molecular weight: 303.36; molecular structure: C19H17N3O. doi:10.1371/journal.pone.0065164.gTo date, studies demonstrating the anticancer activity of PPI and EVO have mainly been done with established cell lines. In the current study, we reported the cytotoxicity effect of PPI and EVO on freshly-removed gastric tumor tissues. To elucidate the mechanisms possibly involved, the expression levels of some associated genes were also determined.Materials and MethodsAll research involving human participants have been approved by the Human Research Protective Committee of Drum Tower Hospital Affiliated to Medical School of Nanjing University and written informed consent was obtained from all patients.specimens included 60 freshly-removed gastric tumors. The study design is shown in Figure 2. Generally speaking, each tumor tissue was divided into two parts once it removed in the surgery: (1) one part was kept in 4uC Hanks’ balanced salt solution with 1 penicillin/streptomycin and detected chemosensitivity in vitro by histoculture drug response assay (HDRA); (2) the rest part was left in formalin and made into formalin-fixed paraffin-embedded (FFPE) tumor blocks for pathological observation and gene detection. Diagnosis of patients with gastric tumor was confirmed by histopa.